Medical devices having multiple layers

ABSTRACT

Described herein are medical devices which are configured for implantation or insertion into a subject, preferably a mammalian subject. The medical devices contain one or more multilayer regions, which contain: (a) one or more (typically a plurality of) charged nanoparticle layers and (b) one or more (typically a plurality of) charged polyelectroyte layers. Such multilayers have a number of desirable attributes, including high strength, non-compliance, and flexibility. Also described herein are methods of making such devices.

FIELD OF THE INVENTION

The present invention relates to the layer-by-layer assembly ofmultilayer regions for implantable and insertable medical devices, andmore particularly, to the formation of multilayer regions that contain aplurality of nanoparticle layers for such devices.

BACKGROUND OF THE INVENTION

Various medical devices are known which are configured for implantationor insertion into a subject. As such theses devices have attendantmechanical requirements.

For example, balloons mounted on the distal ends of catheters are widelyused in medical treatment. A balloon may be used, for example, to widena vessel into which the catheter is inserted or to force open a blockedvessel. The requirements for the strength and size of the balloon varywidely depending on the balloon's intended use and the vessel size intowhich the catheter is inserted. Perhaps the most demanding applicationsfor such balloons are in balloon angioplasty (e.g., percutaneoustransluminal coronary angioplasty or “PCTA”) in which catheters areinserted for long distances into extremely small vessels and are used toopen stenoses of blood vessels by balloon inflation. These applicationsrequire extremely thin-walled, high-strength balloons having predictableinflation properties. Thin walls are necessary, because the balloon'swall thickness limits the minimum diameter of the distal end of thecatheter and therefore determines the ease of passage of the catheterthrough the vascular system and the limits on treatable vessel size.High strength is necessary because the balloon is used to push openstenoses, and the thin wall of the balloon must not burst under the highinternal pressures necessary to accomplish this task (e.g., 10 to 25atmospheres). The balloon elasticity should be relatively low (i.e., theballoon should be substantially non-compliant), so that the diameter iseasily controllable (i.e., small variations in pressure should not causewide variations in diameter, once the balloon is inflated).

As another example, intraluminal stents or stent grafts are commonlyinserted or implanted into body lumens. In one common mode ofimplantation, the stent is provided in a compact state over aninflatable balloon. This assembly is then advanced to the desired sitewithin a body lumen, whereupon the balloon is inflated and the stent orstent graft is expanded to support the vessel walls. In this process,the stent or stent graft is subjected to substantial forces andtherefore must be mechanically robust.

SUMMARY OF THE INVENTION

The above and other challenges are addressed by the present invention.

According to one aspect of the present invention, medical devices areprovided which are configured for implantation or insertion into asubject. The medical devices contain one or more multilayer regions,which contain the following: (a) one or more charged nanoparticle layersand (b) one or more charged polyelectroyte layers.

According to another aspect of the present invention, methods areprovided for making such medical devices. These methods compriseapplying a series of charged layers over a substrate. Each successivelayer in the series is opposite in charge relative to the previouslyapplied layer. Furthermore, the series of charged layers that areapplied over the substrate include the following: (a) one or morecharged nanoparticle layers and (b) one or more charged polyelectroytelayers

An advantage of the present invention is that multilayer medical devicesand medical device components can be provided, which are very thin andflexible, have very high strength, and are substantially non-compliant.

These and other aspects, embodiments and advantages of the presentinvention will become immediately apparent to those of ordinary skill inthe art upon reading the disclosure to follow.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1C are schematic illustrations that show a process for forminga balloon catheter, in accordance with an embodiment of the presentinvention.

FIGS. 2A-2D are schematic illustrations that show a process for forminga stent draft coating, in accordance with another embodiment of thepresent invention.

FIGS. 3A-3C are schematic illustrations that show a process for forminga perfusion balloon catheter, in accordance with another embodiment ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect of the present invention, medical devices areprovided, which are adapted for implantation or insertion into a subjectand which include one or more multilayer regions. The multilayer regionscontain a plurality of alternating, oppositely charged layers, includingthe following: (a) one or more (typically a plurality of) chargednanoparticle layers, each containing charged nanoparticles, and (b) oneor more (typically a plurality of) charged polyelectroyte layers, eachcontaining one or more charged polyelectrolyte species. The nanoparticlelayers and the polyelectrolyte layers have charges that are opposite tothe charges of adjacent layers.

Examples of medical devices for the practice of the present inventioninclude implantable or insertable medical devices, for example,catheters (e.g., renal or vascular catheters such as balloon catheters),guide wires, balloons, filters (e.g., vena cava filters), stents(including coronary vascular stents, cerebral, urethral, ureteral,biliary, tracheal, gastrointestinal and esophageal stents), stentgrafts, cerebral aneurysm filler coils (including Guglilmi detachablecoils and metal coils), vascular grafts, myocardial plugs, patches,pacemakers and pacemaker leads, heart valves, vascular valves, biopsydevices, patches for delivery of therapeutic agent to intact skin andbroken skin (including wounds); tissue engineering scaffolds forcartilage, bone, skin and other in vivo tissue regeneration, as well asany coated substrate (which can comprise, for example, glass, metal,polymer, ceramic and combinations thereof) that is implanted or insertedinto the body.

The medical devices of the present invention include medical devicesthat are used for diagnostics, systemic treatment, or for the localizedtreatment of any mammalian tissue or organ. Examples include tumors;organs including the heart, coronary and peripheral vascular system(referred to overall as “the vasculature”), lungs, trachea, esophagus,brain, liver, kidney, bladder, urethra and ureters, eye, intestines,stomach, pancreas, ovary, and prostate; skeletal muscle; smooth muscle;breast; dermal tissue; cartilage; and bone.

As used herein, “treatment” refers to the prevention of a disease orcondition, the reduction or elimination of symptoms associated with adisease or condition, or the substantial or complete elimination adisease or condition. Typical subjects are mammalian subjects, moretypically human subjects.

The multilayer regions of the present invention can be assembled usinglayer-by-layer techniques. Layer-by-layer techniques can be used to coata wide variety of substrates using charged materials via electrostaticself-assembly. In the layer-by-layer technique, a first layer having afirst surface charge is typically deposited on an underlying substrate,followed by a second layer having a second surface charge that isopposite in sign to the surface charge of the first layer, and so forth.The charge on the outer layer is reversed upon deposition of eachsequential layer.

Substrates for the practice of the present invention include substratesthat are incorporated into the finished medical device, as well assubstrates that merely acts as templates for the layer-by-layertechnique, but which are not found in the finished device (although aresidue of the substrate will remain in certain embodiments). Thesubstrates are commonly formed from ceramic, metallic, polymeric andother high molecular weight materials, including stable anddisintegrable materials.

Ceramic substrates may be selected, for example, from substratescontaining one or more of the following: metal oxides, includingaluminum oxides and transition metal oxides (e.g., oxides of titanium,zirconium, hafnium, tantalum, molybdenum, tungsten, rhenium, andiridium); silicon-based ceramics, such as those containing siliconnitrides, silicon carbides and silicon oxides (sometimes referred to asglass ceramics); calcium phosphate ceramics (e.g., hydroxyapatite); andcarbon-based, ceramic-like materials such as carbon nitrides.

Metallic substrates may be selected, for example, from substratescontaining one or more of the following: metal alloys such ascobalt-chromium alloys, nickel-titanium alloys (e.g., nitinol),cobalt-chromium-iron alloys (e.g., elgiloy alloys), nickel-chromiumalloys (e.g., inconel alloys), and iron-chromium alloys (e.g., stainlesssteels, which contain at least 50% iron and at least 11.5% chromium),and noble metals such as silver, gold, platinum, palladium, iridium,osmium, rhodium, titanium, tungsten, and ruthenium.

Substrates containing polymers and other high molecular weight materialsmay be selected, for example, from substrates containing one or more ofthe following: polycarboxylic acid polymers and copolymers includingpolyacrylic acids; acetal polymers and copolymers; acrylate andmethacrylate polymers and copolymers (e.g., n-butyl methacrylate);cellulosic polymers and copolymers, including cellulose acetates,cellulose nitrates, cellulose propionates, cellulose acetate butyrates,cellophanes, rayons, rayon triacetates, and cellulose ethers such ascarboxymethyl celluloses and hydroxyalkyl celluloses; polyoxymethylenepolymers and copolymers; polyimide polymers and copolymers such aspolyether block imides, polyamidimides, polyesterimides, andpolyetherimides; polysulfone polymers and copolymers includingpolyarylsulfones and polyethersulfones; polyamide polymers andcopolymers including nylon 6,6, nylon 12, polyether-block co-polyamidepolymers (e.g., Pebax® resins), polycaprolactams and polyacrylamides;resins including alkyd resins, phenolic resins, urea resins, melamineresins, epoxy resins, allyl resins and epoxide resins; polycarbonates;polyacrylonitriles; polyvinylpyrrolidones (cross-linked and otherwise);polymers and copolymers of vinyl monomers including polyvinyl alcohols,polyvinyl halides such as polyvinyl chlorides, ethylene-vinylacetatecopolymers (EVA), polyvinylidene chlorides, polyvinyl ethers such aspolyvinyl methyl ethers, vinyl aromatic polymers and copolymers such aspolystyrenes, styrene-maleic anhydride copolymers, vinylaromatic-hydrocarbon copolymers including styrene-butadiene copolymers,styrene-ethylene-butylene copolymers (e.g., apolystyrene-polyethylene/butylene-polystyrene (SEBS) copolymer,available as Kraton® G series polymers), styrene-isoprene copolymers(e.g., polystyrene-polyisoprene-polystyrene), acrylonitrile-styrenecopolymers, acrylonitrile-butadiene-styrene copolymers,styrene-butadiene copolymers and styrene-isobutylene copolymers (e.g.,polyisobutylene-polystyrene block copolymers such as SIBS), polyvinylketones, polyvinylcarbazoles, and polyvinyl esters such as polyvinylacetates; polybenzimidazoles; ionomers; polyalkyl oxide polymers andcopolymers including polyethylene oxides (PEO); polyesters includingpolyethylene terephthalates, polybutylene terephthalates and aliphaticpolyesters such as polymers and copolymers of lactide (which includeslactic acid as well as d-, l- and meso lactide), epsilon-caprolactone,glycolide (including glycolic acid), hydroxybutyrate, hydroxyvalerate,para-dioxanone, trimethylene carbonate (and its alkyl derivatives),1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and6,6-dimethyl-1,4-dioxan-2-one (a copolymer of polylactic acid andpolycaprolactone is one specific example); polyether polymers andcopolymers including polyarylethers such as polyphenylene ethers,polyether ketones, polyether ether ketones; polyphenylene sulfides;polyisocyanates; polyolefin polymers and copolymers, includingpolyalkylenes such as polypropylenes, polyethylenes (low and highdensity, low and high molecular weight), polybutylenes (such aspolybut-1-ene and polyisobutylene), polyolefin elastomers (e.g.,santoprene), ethylene propylene diene monomer (EPDM) rubbers,poly-4-methyl-pen-1-enes, ethylene-alpha-olefin copolymers,ethylene-methyl methacrylate copolymers and ethylene-vinyl acetatecopolymers; fluorinated polymers and copolymers, includingpolytetrafluoroethylenes (PTFE),poly(tetrafluoroethylene-co-hexafluoropropene) (FEP), modifiedethylene-tetrafluoroethylene copolymers (ETFE), and polyvinylidenefluorides (PVDF); silicone polymers and copolymers; polyurethanes;p-xylylene polymers; polyiminocarbonates; copoly(ether-esters) such aspolyethylene oxide-polylactic acid copolymers; polyphosphazines;polyalkylene oxalates; polyoxaamides and polyoxaesters (including thosecontaining amines and/or amido groups); polyorthoesters; biopolymers,such as polypeptides, proteins, polysaccharides and fatty acids (andesters thereof), including fibrin, fibrinogen, collagen, elastin,chitosan, gelatin, starch, glycosaminoglycans such as hyaluronic acid,various waxes, including low melting point waxes used for dentalengineering (e.g., for so-called “lost wax” techniques); as well asblends and further copolymers of the above.

Certain substrates are inherently charged and thus readily lendthemselves to layer-by-layer assembly.

To the extent that the substrate does not have an inherent net surfacecharge, a surface charge may nonetheless be provided. For example, wherethe substrate to be coated is conductive, a surface charge can beprovided by applying an electrical potential to the same. Once a firstpolyelectrolyte layer is established in this fashion, a secondpolyelectrolyte layer having a second surface charge that is opposite insign to the surface charge of the first polyelectrolyte layer canreadily be applied, and so forth.

As another example, the substrate can be provided with a positive chargeby covalently attaching functional groups having positive charge (e.g.,amine, imine or another basic groups) or functional groups having anegative charge (e.g., carboxylic, phosphonic, phosphoric, sulfuric,sulfonic, or other acid groups) using methods well known in the art.

As another example, a surface charge can be provided on a substrate byexposing the substrate to a charged amphiphilic substance. Amphiphilicsubstances include any substance having hydrophilic and hydrophobicgroups. Where used, the amphiphilic substance should have at least oneelectrically charged group to provide the substrate surface with a netelectrical charge. Therefore, the amphiphilic substances that are usedherein can also be referred to as an ionic amphiphilic substances.

Amphiphilic polyelectrolytes are used as ionic amphiphilic substances insome embodiments. For example, a polyelectrolyte comprising chargedgroups (which are hydrophilic) as well as hydrophobic groups, such aspolyethylenimine (PEI) or poly(styrene sulfonate) (PSS), can beemployed. Cationic and anionic surfactants are also used as amphiphilicsubstances in some embodiments. Cationic surfactants include quaternaryammonium salts (R₄N⁺X⁻), where R is an organic radical and where X⁻ is acounter-anion, e.g. a halogenide, for example, didodecyldimethylammoniumbromide (DDDAB), alkyltrimethylammonium bromides such ashexadecyltrimethylammonium bromide (HDTAB), dodecyltrimethylammoniumbromide (DTMAB), myristyltrimethylammonium bromide (MTMAB), or palmityltrimethylammonium bromide, or N-alkylpyridinium salts, or tertiaryamines (R₃NH⁺X⁻), for example,cholesteryl-3β-N-(dimethyl-aminoethyl)-carbamate or mixtures thereof.Anionic surfactants include alkyl or olefin sulfate (R—OSO₃M), forexample, a dodecyl sulfate such as sodium dodecyl sulfate (SDS), alauryl sulfate such as sodium lauryl sulfate (SLS), or an alkyl orolefin sulfonate (R—SO₃M), for example, sodium-n-dodecyl-benzenesulfonate, or fatty acids (R—COOM), for example, dodecanoic acid sodiumsalt, or phosphoric acids or cholic acids or fluoro-organics, forexample, lithium-3-[2-(perfluoroalkyl)ethylthio]propionate or mixturesthereof, where R is an organic radical and M is a counter-cation.

Hence, in some embodiments, a surface charge is provided on a substrateby adsorbing cations (e.g., protamine sulfate, polyallylamine,polydiallyldimethylammonium species, polyethyleneimine, chitosan,gelatin, spermidine, albumin, among many others) or by adsorbing anions(e.g., polyacrylic acid, sodium alginate, polystyrene sulfonate,eudragit, gelatin [gelatin is an amphiphilic polymer, hence it fits inboth categories depending how it is being prepared], hyaluronic acid,carrageenan, chondroitin sulfate, carboxymethylcellulose, among manyothers) to the surface of the substrate as a first charged layer.Although full coverage may not be obtained for the first layer, onceseveral layers have been deposited, a full coverage should ultimately beobtained, and the influence of the substrate is expected to benegligible. The feasibility of this process has been demonstrated onglass substrates using charged polymeric (polyelectrolyte) materials.See, e.g., “Multilayer on solid planar substrates,” Multi-layer thinfilms, sequential assembly of nanocomposite materials, Wiley-VCH ISBN3-527-30440-1, Chapter 14; and “Surface-chemistry technology formicrofluidics,” Hau, Winky L. W. et al. J. Micromech. Microeng. 13(2003) 272-278.

The species for establishing a surface charge can be applied to thesubstrate by a variety of techniques. These techniques include, forexample, spraying techniques, dipping techniques, roll and brush coatingtechniques, techniques involving coating via mechanical suspension suchas air suspension, ink jet techniques, spin coating techniques, webcoating techniques and combinations of these processes. The choice ofthe technique will depend on the requirements at hand. For example,dipping and spraying techniques (without masking) can be employed, forinstance, where it is desired to apply the species to an entiresubstrate. On the other hand, roll coating, brush coating and ink jetprinting can be employed, for instance, where it is desired to apply thespecies only certain portions of the substrate (e.g., in the form of apattern).

Once a sufficient charge is provided on a substrate, it can be readilycoated with a layer of an oppositely charged material. Multilayerregions are formed by repeated treatment with alternating, oppositelycharged materials, i.e., by alternating treatment with materials thatprovide positive and negative surface charges. The layers self-assembleby means of electrostatic layer-by-layer deposition, thus forming amultilayered region over the substrate.

As noted above, the multilayer regions of the present inventiontypically include the following: (a) a plurality of charged nanoparticlelayers, which contain charged nanoparticles, and (b) a plurality ofcharged polyelectroyte layers, which contain one or more chargedpolyelectrolyte species.

The nanoparticles for use in the charged nanoparticle layers of thepresent invention can vary widely in size, but typically have at leastone dimension (e.g., the thickness for a nanoplates, the diameter for ananospheres, nanocylinders and nanotubes, etc.) that is less than 1000nm, more typically less than 100 nm. Hence, for example, nanoplatestypically have at least one dimension that is less than 1000 nm,nanofibers typically have at least two orthogonal dimensions (e.g., thediameter for cylindrical nanofibers) that are less than 1000 nm, whileother nanoparticles typically have three orthogonal dimensions that areless than 1000 nm (e.g., the diameter for nanospheres).

A wide variety of nanoparticles are available for use in the chargednanoparticle layers of the present invention including, for example,carbon, ceramic and metallic nanoparticles including nanoplates,nanotubes, and nanospheres, and other nanoparticles. Specific examplesof nanoplates include synthetic or natural phyllosilicates includingclays and micas (which may optionally be intercalated and/or exfoliated)such as montmorillonite, hectorite, hydrotalcite, vermiculite andlaponite. Specific examples of nanotubes and nanofibers includesingle-wall, so-called “few-wall,” and multi-wall carbon nanotubes, suchas fullerene nanotubes, vapor grown carbon fibers, alumina nanofibers,titanium oxide nanofibers, tungsten oxide nanofibers, tantalum oxidenanofibers, zirconium oxide nanofibers, and silicate nanofibers such asaluminum silicate nanofibers. Specific examples of further nanoparticles(e.g., nanoparticles having three orthogonal dimensions that are lessthan 1000 nm) include fullerenes (e.g., “Buckey balls”), silicananoparticles, aluminum oxide nanoparticles, titanium oxidenanoparticles, tungsten oxide nanoparticles, tantalum oxidenanoparticles, zirconium oxide nanoparticles, dendrimers, and monomericsilicates such as polyhedral oligomeric silsequioxanes (POSS), includingvarious functionalized POSS and polymerized POSS.

One preferred group of nanoparticles for the practice of the presentinvention are carbon nanotubes and carbon nanofibers having a diameterranging from 0.5 nm to 200 nm.

In this regard, carbon nanotubes, especially single-wall carbonnanotubes (SWNT), have remarkable mechanical properties, and show greatpromise for enhancing strength in composites, such as polymercomposites. SWNT polymer composites are commonly prepared by polymerblending or by in situ polymerization techniques. Unfortunately, evenwith surface modification of the SWNT, phase separation is problematicdue to the vastly different molecular mobilities of the components. Toovercome phase separation issues between the SWNT and the polymer,layer-by-layer assembly has been used in which alternating layers ofSWNT and polymeric material have been deposited. See Arif A. Mamedov etal., “Molecular design of strong single-wall carbonnanotube/polyelectrolyte multilayer composites,” Nature Material, Vol.1, No. 3, 2002, pages 191-194, the entire disclosure of which isincorporated by reference.

As with the substrate, various techniques are available for providingcharges on nanoparticles that are not inherently charged. For example, asurface charge can be provided by adsorbing or otherwise attachingspecies on the nanoparticles which have a net positive or negativecharge, for example, charged amphiphilic substance such as amphiphilicpolyelectrolytes and cationic and anionic surfactants (see above).Moreover, where the nanoparticles are sufficiently stable, surfacecharges can sometimes be established by exposure to highly acidicconditions. For example, it is known that carbon nanoparticles, such ascarbon nanotubes, can be partially oxidized by refluxing in strong acidto form carboxylic acid groups (which ionize to become negativelycharged carboxyl groups) on the nanoparticles. Establishing a surfacecharge on nanoparticles is also advantageous in that a relatively stableand uniform suspension of the nanoparticles is commonly achieved, due atleast in part to electrostatic stabilization effects.

With respect to polyelectrolyte species, a wide variety of thesematerials are also available for use in forming charged polyelectrolytelayers in accordance with the present invention. Polyelectrolytes arepolymers having charged (e.g., ionically dissociable) groups. Usually,the number of these groups in the polyelectrolytes is so large that thepolymers are soluble in polar solvents (including water) when inionically dissociated form (also called polyions). Depending on the typeof dissociable groups, polyelectrolytes are typically classified aspolyacids and polybases. When dissociated, polyacids form polyanions,with protons being split off. Polyacids include inorganic, organic andbio-polymers. Examples of polyacids are polyphosphoric acids,polyvinylsulfuric acids, polyvinylsulfonic acids, polyvinylphosphonicacids and polyacrylic acids. Examples of the corresponding salts, whichare also called polysalts, are polyphosphates, polyvinylsulfates,polyvinylsulfonates, polyvinylphosphonates and polyacrylates. Polybasescontain groups which are capable of accepting protons, e.g., by reactionwith acids, with a salt being formed. Examples of polybases havingdissociable groups within their backbone and/or side groups arepolyallylamine, polyethylimine, polyvinylamine and polyvinylpyridine. Byaccepting protons, polybases form polycations. Some polyelectrolyteshave both anionic and cationic groups, but nonetheless have a netpositive or negative charge.

Suitable polyelectrolytes for use in accordance with the inventioninclude those based on biopolymers, for example, alginic acid, gummiarabicum, nucleic acids, pectins and proteins, chemically modifiedbiopolymers such as carboxymethyl cellulose and lignin sulfonates, andsynthetic polymers such as polymethacrylic acid, polyvinylsulfonic acid,polyvinylphosphonic acid and polyethylenimine. Linear or branchedpolyelectrolytes can be used in some embodiments. Using branchedpolyelectrolytes can lead to less compact polyelectrolyte multilayershaving a higher degree of wall porosity. Polyelectrolyte molecules canbe crosslinked within or/and between the individual layers in someembodiments, e.g. by crosslinking amino groups with aldehydes, forexample, to increase stability. Furthermore, amphiphilicpolyelectrolytes, e.g., amphiphilic block or random copolymers havingpartial polyelectrolyte character, can be used in some embodiments toaffect permeability towards polar small molecules.

Suitable polyelectrolytes include low-molecular weight polyelectrolytes(e.g., polyelectrolytes having molecular weights of a few hundredDaltons) up to macromolecular polyelectrolytes (e.g., polyelectrolytesof synthetic or biological origin, which commonly have molecular weightsof several million Daltons).

Specific examples of polyelectrolyte cations (polycations) includeprotamine sulfate polycations, poly(allylamine) polycations (e.g.,poly(allylamine hydrochloride) (PAH)), polydiallyldimethylammoniumpolycations, polyethyleneimine polycations, chitosan polycations,gelatin polycations, spermidine polycations and albumin polycations.Specific examples of polyelectrolyte anions (polyanions) includepoly(styrenesulfonate) polyanions (e.g., poly(sodium styrene sulfonate)(PSS)), polyacrylic acid polyanions, sodium alginate polyanions,eudragit polyanions, gelatin polyanions, hyaluronic acid polyanions,carrageenan polyanions, chondroitin sulfate polyanions, andcarboxymethylcellulose polyanions.

In some embodiments, biodisintegrable polyelectrolytes are utilized. Forexample, by using polyelectrolytes that are biodisintegrable near theouter surface of the multilayer region, a therapeutic agent can bereleased into the subject at a rate that is dependent upon the rate ofdisintegration of the polyelectrolyte layers. As used herein, a“biodisintegrable material” is a material which undergoes dissolution,degradation, resorption and/or other disintegration processes over theperiod that the device is designed to reside in a patient. Conversely,in some embodiments, biostable polyelectrolytes are utilized. As usedherein, a “biostable material” is a material which does not undergosubstantial dissolution, degradation, resorption and/or otherdisintegration processes over the period that the device is designed toreside in a patient.

Examples of biodisintegrable and biostable polyelectrolytes includepolyglycolic acid (PGA), polylactic acid (PLA), polyamides,poly-2-hydroxy-butyrate (PHB), polycaprolactone (PCL),poly(lactic-co-glycolic)acid (PLGA), protamine sulfate, polyallylamine,polydiallyldimethylammonium species, polyethyleneimine, chitosan,eudragit, gelatin, spermidine, albumin, polyacrylic acid, sodiumalginate, polystyrene sulfonate, hyaluronic acid, carrageenan,chondroitin sulfate, carboxymethylcellulose, heparin, other polypeptidesand proteins, and DNA, among others.

In some embodiments of the invention, at least one therapeutic agent isdisposed on or within the polyelectrolyte multilayer region of themedical devices of the present invention. Several techniques areavailable for establishing the therapeutic agent within the multilayerregion.

In some embodiments, the therapeutic agent is charged, for example,because it is itself a charged molecule or because it is intimatelyassociated with a charged molecule. Examples of charged therapeuticagents include small molecule and polymeric therapeutic agentscontaining ionically dissociable groups, for example, therapeutic agentscontaining carboxylic, phosphonic, phosphoric, sulfuric, sulfonic, orother acid groups, or therapeutic agents containing amine, imine oranother basic groups. As noted above, acidic groups generally becomeanionic groups in aqueous solution by donating protons, while basicgroups generally become cations by accepting protons. In some cases, thetherapeutic agent will contain both acidic and basic groups, yet willhave a net (overall) charge. Examples of charged therapeutic agentsinclude polynucleotides (e.g., DNA and RNA), polypeptides (e.g.,proteins, whose overall net charge will vary with pH, based on theirrespective isoelectric points), and various small molecule drugs, amongothers. For example, insulin is a negatively charged molecule at neutralpH, while protamine is positively charged. Other examples includeheparin, hyaluronan, immunogloubulins and so forth.

Even where the therapeutic agent does not possess one or more chargedgroups, it can nevertheless be provided with a charge, for example,through non-covalent association with a charged species. Examples ofnon-covalent associations include hydrogen bonding,hydrophilic/lipophilic interactions, and so forth. For instance, thetherapeutic agent can be associated with an ionic amphiphilic substance,such as one of those set forth above.

In certain embodiments where a charged therapeutic agent is employed,one or more layers of the charged therapeutic agent is/are depositedduring the course of assembling the multilayer region. For example, insome instances, the therapeutic agent is itself a polyelectrolyte (e.g.,where the therapeutic agent is a polypeptide or a polynucleotide) and itis used, as such, to create one or more polyelectrolyte layers withinthe multilayer region. In other instances, the charged therapeutic agentis not a polyelectrolyte (e.g., it may be a charged small moleculedrug). Nevertheless, one or more layers of the charged therapeutic agentcan be substituted for one or more layers of the same charge (i.e.,positive or negative) during the multilayer assembly process. In each ofthe above cases, the therapeutic agent is disposed on and/or within themultilayer region.

In still other embodiments, the therapeutic agent is provided withincharged nanocapsules, which are formed, for example, usinglayer-by-layer techniques such as those described herein and in commonlyassigned U.S. Ser. No. 10/768,388, entitled “Localized Drug DeliveryUsing Drug-Loaded Nanocapsules,” the entire disclosure of which isincorporated by reference. In these embodiments, one or more layers ofthe charged nanocapsules can be deposited during the course ofassembling the multilayer region.

In still other embodiments, the multilayer region is loaded withtherapeutic agent subsequent to its formation. In this regard, varioustechniques have been reported for incorporating therapeutic agents intopre-formed microscopic polyelectrolyte multilayer capsules, and thesetechniques are equally applicable to the multilayer-coated structures ofthe present invention.

For example, techniques are known in the polyelectrolyte multilayer artfor increasing the porosity, and thus the permeability, ofpolyelectrolyte multilayer structures. For instance, techniques havebeen reported for introducing different materials into polyelectrolytemultilayer capsules by varying the pH. In particular, polyelectrolytemultilayer structures are known (e.g. PSS-PAH multilayer structures)which are effectively closed at higher pH's. However, at more acidicpH's (e.g., pH 6 and below), the multilayer structures open up, allowingmacromolecules (e.g., FITC-labeled dextran, MW˜75,000 and MW˜2,000,000as well as FITC-labeled albumin have been demonstrated) to freelypermeate the capsule. See, e.g., Antipov, A. A. et al., “Polyelectrolytemultilayer capsule permeability control,” Colloids and Surfaces A:Physicochemical and Engineering Aspects, 198-200 (2002) pp. 535-541.

In the present invention, layer-by-layer assembly is preferablyconducted by exposing a selected charged substrate to solutions orsuspensions that contain species of alternating net charge, includingsolutions or suspensions that contain charged nanoparticles, chargedpolyelectrolytes, and, optionally, charged therapeutic agents. Theconcentration of the charged entities within these solutions andsuspensions can vary widely, but will commonly be in the range of from0.01 to 10 mg/ml, and more commonly from 0.1 to 1 mg/ml. Moreover the pHof these suspensions and solutions are such that the nanoparticles,polyelectrolytes, and optional therapeutic agents maintain their desiredcharge. Buffer systems may be employed for this purpose, if needed,although the charged entities chosen are commonly ionized at neutral pH(e.g., at pH 6-8) or at the pH of the body location where the device isto be inserted or implanted.

The solutions and suspensions containing the charged species (e.g.,solutions/suspensions of polyelectrolytes, charged nanoparticles, orother optional charged species such as charged therapeutic agents) canbe applied to the charged substrate surface using a variety oftechniques including, for example, spraying techniques, dippingtechniques, roll and brush coating techniques, techniques involvingcoating via mechanical suspension such as air suspension, ink jettechniques, spin coating techniques, web coating techniques andcombinations of these processes. As a specific example, layers can beapplied over an underlying substrate by immersing the entire substrateinto a solution or suspension containing the charged species, or byimmersing half of the substrate into the solution or suspension,flipping the same, and immersing the other half of the substrate intothe solution or suspension to complete the coating. In some embodiments,the substrate is rinsed after application of each charged species layer,for example, using a washing solution that has a pH that will ensurethat the charge of the outer layer is maintained.

Using these and other techniques, multiple layers of alternating chargeare applied over the underlying substrate, including the application ofone or more (typically a plurality of) charged nanoparticle layers andthe application of one or more (typically a plurality of) chargedpolyelectroyte layers. For example, in some embodiments, between 10 and200, more typically between 30 and 100 layers are applied over thesubstrate. The total thickness of the multilayer region that isassembled will typically range, for example, from 10 nanometers to 40micrometers (microns), more typically between 100 nanometers and 10microns.

In many beneficial embodiments, the multilayer region comprises analternating series of negatively charged nanoparticle layers andpositively charged polyelectroyte layers. In other beneficialembodiments, the multilayer region comprises an alternating series ofpositively charged nanoparticle layers and negatively chargedpolyelectroyte layers. In still other beneficial embodiments, themultilayer region comprises an alternating series of positively andnegatively charged nanoparticle layers. One class of nanoparticles thatcome both in positively and negatively charged forms are dendrimers.

One preferred material for use in forming charged polyelectroyte layersin accordance with the present invention is polyethyleneimine (PEI),which, as noted above, is an amphiphilic polyelectrolyte and thus isuseful for establishing an initial charged layer on a substrate and canbe used to provide subsequent polyelectrolyte layers as well. Beingpositively charged, PEI is useful in combination with adjacent layersthat contain negatively charged species, for example, carboxylfunctionalized carbon nanotubes. PEI having a molecular weight of about70,000 is readily available from Sigma Aldrich. For example, to form amultilayer stack, the substrate can be dipped in a solution of PEI,followed by dipping in a suspension of carbon nanotubes, and so forth,with the number of alternating layers established ultimately depending,for example, upon the desired thickness and strength of the finalmultilayer region.

The PEI layer can also be followed by a layer of a negatively chargedpolyelectrolyte such as polyacrylic acid (PAA). The negatively chargedpolyelectrolyte is useful, for instance, in combination with adjacentlayers that contain positively charged species, such as positivelycharged nanoparticles, for example dendrimers and functionalized goldnanoparticles, or additional PEI layers (e.g., where it is desired toestablish multiple polyelectrolyte layers beneath, between or above thenanoparticle layers).

With respect to functionalized gold nanoparticles, it is noted thatthese particles could help to create a radio-opaque layer. Goldnanoparticles can be made positively charged by applying a outer layerof lysine to the same. See, for example, “DNA-mediated electrostaticassembly of gold nanoparticles into linear arrays by a simpledrop-coating procedure,” Murali Sastrya and Ashavani Kumar, AppliedPhysics Letters, Vol. 78, No. 19, 7 May 2001.

The bonding between a substrate and PEI can be enhanced, for example, byproviding as substrate with negatively charged groups. For example, aPebax® balloon surface can be modified to have a negative charge byproviding the balloon with negatively charged functional groups such ascarboxylate groups.

As noted above, in some embodiments, a multilayer region is formed uponan underlying substrate that becomes incorporated into the finishedmedical device. As one specific example, a multilayer region withreinforcement properties in accordance with the present invention can bebuilt upon a preexisting balloon, such as a Pebax® balloon.

In some embodiments, on the other hand, the underlying substrate merelyacts as a template (e.g., as a mold) for application of thelayer-by-layer technique, and the multilayer region is freed from thesubstrate after forming the multilayer region. The multilayer region isapplied in some instance to the inside of the removable substrate, andis applied in other instances to the outside of the removable substrate.

In some cases, the removable substrate is releasably engaged with themultilayer region, for example, by forming a weak (dissolvable) firstelectrostatic layer on top the substrate. As another example, hollowcapsules have been formed by forming a series of polyelectrolytemultilayers around cores of melamine formaldehyde or manganesecarbonate, followed by removal of the core material by dissolution. SeeSukhorukov et al., “Comparative Analysis of Hollow and FilledPolyelectrolyte Microcapsules Templated on Melamine Formaldehyde andCarbonate Cores,” Macromol. Chem. Phys., 205, 2004, pp. 530-535. Usinganalogous procedures, a layer of melamine formaldehyde or manganesecarbonate is formed on a removable substrate. After forming the desiredpolyelectrolyte layers on the substrate, the layer of melamineformaldehyde or manganese carbonate is dissolved, releasing thesubstrate. The substrate can be in the form, for instance, of a reusableone-piece or multi-piece (e.g. two-piece) mold, as is known in the art.

In other cases, the substrate is removed by destroying it, for example,by melting, sublimation, combustion, dissolution or other process, inorder to free the multilayer region. For instance, in some embodiments,a so-called “lost core” mold is used. These molds can be made, forexample, from materials that melt at moderately elevated temperatures(e.g., 60° C.), for instance, dental waxes such as those available fromMDL Dental Products, Inc., Seattle, Wash., USA. Other examples ofmaterials that can be used for the formation of destroyable molds arematerials that are essentially insoluble in cold water, but are solublein hot water. Polyvinyl alcohol (PVOH) is one example of such amaterial.

Where the multilayer region is provided over a substrate, it can extendover all or only a portion of the substrate. For example, multilayerregions can be provided over multiple surface portions of an underlyingsubstrate and may be provided in any shape or pattern (e.g., in the formof a series of rectangles, stripes, or any other continuous ornon-continuous pattern). Techniques by which patterned multilayerregions may be provided are described above and include ink jettechniques, roll coating techniques, etc. For example, in someembodiments, a patterned multilayer region is created, to providedifferences in strength or functionality across the medical device.

In some embodiments, one or more reinforcement members are providedadjacent to or within the multilayer regions of the present invention.For example, in some cases, one or more reinforcement members areapplied to an underlying substrate, followed by a series ofpolyelectrolyte and nanoparticle layers. As another example, in somecases, a first series of polyelectrolyte layers or a first series ofboth polyelectrolyte and nanoparticle layers are provided, followed bythe application of one or more reinforcement members, followed by asecond series of polyelectrolyte layers or a second series of bothpolyelectrolyte and nanoparticle layers.

Examples of reinforcement members include fibrous reinforcement memberssuch as metal fiber meshes, metal fiber braids, metal fiber windings,intermingled fibers (e.g., metal fiber, carbon fibers, high densitypolyethylene fibers, liquid polymer crystals) and so forth. Metals thatcan be used for this purpose include, for example, various metals listedabove for use in forming metallic substrates. For example, very finesteel wire is available from Bekaert (Belgium) for use as areinforcement member. If desired, the reinforcement members can beprovided with a surface charge to enhance incorporation of thereinforcement members onto or into the multilayer regions. For example,layer-by-layer techniques such as those described herein can be used toencapsulate the reinforcement members, thereby providing them with acharged outer layer and enhancing interaction of the reinforcementmembers with an adjacent layer (e.g., a polyelectrolyte or nanoparticlelayer) of opposite charge.

A variety of outer top layers can be provided for the multilayer regionsof the present invention. For instance, in some embodiments, the outertop layer is a charged nanoparticle layer, a charged polyelectrolytelayer, charged therapeutic agent layer, and so forth. As a specificexample, the outer top layer can be a carbon nanoparticle layer (e.g., alayer of charged carbon nanotubes, C60 “Buckey balls”, etc.).

In other embodiments, an outer polymer layer is provided over themultilayer region (e.g., using conventional thermoplastic or solventprocessing techniques) to protect the outer surface of the multilayerregion and to contain any debris in the unlikely event that themultilayer region becomes damaged (e.g., in the unlikely event of aballoon burst). Such polymer layers can be selected from the variouspolymeric materials described above for use in connection withsubstrates.

As indicated above, in some embodiments of the invention, one or moretherapeutic agents are incorporated onto or into the multilayer region,giving the medical device, for example, a drug releasing function uponimplantation.

Therapeutic agents may be used singly or in combination in the medicaldevices of the present invention. “Drugs,” “therapeutic agents,”“pharmaceutically active agents,” “pharmaceutically active materials,”and other related terms may be used interchangeably herein. These termsinclude genetic therapeutic agents, non-genetic therapeutic agents andcells.

Exemplary non-genetic therapeutic agents for use in connection with thepresent invention include: (a) anti-thrombotic agents such as heparin,heparin derivatives, urokinase, and PPack (dextrophenylalanine prolinearginine chloromethylketone); (b) anti-inflammatory agents such asdexamethasone, prednisolone, corticosterone, budesonide, estrogen,sulfasalazine and mesalamine; (c)antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel,5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones,endostatin, angiostatin, angiopeptin, monoclonal antibodies capable ofblocking smooth muscle cell proliferation, and thymidine kinaseinhibitors; (d) anesthetic agents such as lidocaine, bupivacaine andropivacaine; (e) anti-coagulants such as D-Phe-Pro-Arg chloromethylketone, an RGD peptide-containing compound, heparin, hirudin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, aspirin, prostaglandininhibitors, platelet inhibitors and tick antiplatelet peptides; (f)vascular cell growth promoters such as growth factors, transcriptionalactivators, and translational promotors; (g) vascular cell growthinhibitors such as growth factor inhibitors, growth factor receptorantagonists, transcriptional repressors, translational repressors,replication inhibitors, inhibitory antibodies, antibodies directedagainst growth factors, antibodies recognizing receptors on endothelialprogenitor cells, proteins of the tetraspanin family, such as CD9 Beta-1and Beta-3 integrins, CD63, CD81, FcgammaRII, bifunctional moleculesconsisting of a growth factor and a cytotoxin, bifunctional moleculesconsisting of an antibody and a cytotoxin; (h) protein kinase andtyrosine kinase inhibitors (e.g., tyrphostins, genistein, quinoxalines);(i) prostacyclin analogs; (j) cholesterol-lowering agents; (k)angiopoietins; (l) antimicrobial agents such as triclosan,cephalosporins, aminoglycosides and nitrofurantoin; (m) cytotoxicagents, cytostatic agents and cell proliferation affectors; (n)vasodilating agents; (o) agents that interfere with endogenousvasoactive mechanisms; (p) inhibitors of leukocyte recruitment, such asmonoclonal antibodies; (q) cytokines; and (r) hormones.

Preferred non-genetic therapeutic agents include paclitaxel, sirolimus,everolimus, tacrolimus, dexamethasone, estradiol, ABT-578 (AbbottLaboratories), trapidil, liprostin, Actinomcin D, Resten-NG, Ap-17,abciximab, clopidogrel and Ridogrel.

Exemplary genetic therapeutic agents for use in connection with thepresent invention include anti-sense DNA and RNA as well as DNA codingfor the various proteins (as well as the proteins themselves): (a)anti-sense RNA, (b) tRNA or rRNA to replace defective or deficientendogenous molecules, (c) angiogenic and other factors including growthfactors such as acidic and basic fibroblast growth factors, vascularendothelial growth factor, endothelial mitogenic growth factors,epidermal growth factor, transforming growth factor α and β,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor α, hepatocyte growth factor andinsulin-like growth factor, (d) cell cycle inhibitors including CDinhibitors, and (e) thymidine kinase (“TK”) and other agents useful forinterfering with cell proliferation. Also of interest is DNA encodingfor the family of bone morphogenic proteins (“BMP's”), including BMP-2,BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10,BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferredBMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. Thesedimeric proteins can be provided as homodimers, heterodimers, orcombinations thereof, alone or together with other molecules.Alternatively, or in addition, molecules capable of inducing an upstreamor downstream effect of a BMP can be provided. Such molecules includeany of the “hedgehog” proteins, or the DNA's encoding them.

Vectors for delivery of genetic therapeutic agents include viral vectorssuch as adenoviruses, gutted adenoviruses, adeno-associated virus,retroviruses, alpha virus (Semliki Forest, Sindbis, etc.), lentiviruses,herpes simplex virus, replication competent viruses (e.g., ONYX-015) andhybrid vectors; and non-viral vectors such as artificial chromosomes andmini-chromosomes, plasmid DNA vectors (e.g., pCOR), cationic polymers(e.g., polyethyleneimine, polyethyleneimine (PEI)), graft copolymers(e.g., polyether-PEI and polyethylene oxide-PEI), neutral polymers PVP,SP1017 (SUPRATEK), lipids such as cationic lipids, liposomes,lipoplexes, nanoparticles, or microparticles, with and without targetingsequences such as the protein transduction domain (PTD).

Cells for use in connection with the present invention include cells ofhuman origin (autologous or allogeneic), including whole bone marrow,bone marrow derived mono-nuclear cells, progenitor cells (e.g.,endothelial progenitor cells), stem cells (e.g., mesenchymal,hematopoietic, neuronal), pluripotent stem cells, fibroblasts,myoblasts, satellite cells, pericytes, cardiomyocytes, skeletal myocytesor macrophage, or from an animal, bacterial or fungal source(xenogeneic), which can be genetically engineered, if desired, todeliver proteins of interest.

Numerous therapeutic agents, not necessarily exclusive of those listedabove, have been identified as candidates for vascular treatmentregimens, for example, as agents targeting restenosis. Such agents areuseful for the practice of the present invention and include one or moreof the following: (a) Ca-channel blockers including benzothiazapinessuch as diltiazem and clentiazem, dihydropyridines such as nifedipine,amlodipine and nicardapine, and phenylalkylamines such as verapamil, (b)serotonin pathway modulators including: 5-HT antagonists such asketanserin and naftidrofuryl, as well as 5-HT uptake inhibitors such asfluoxetine, (c) cyclic nucleotide pathway agents includingphosphodiesterase inhibitors such as cilostazole and dipyridamole,adenylate/Guanylate cyclase stimulants such as forskolin, as well asadenosine analogs, (d) catecholamine modulators including α-antagonistssuch as prazosin and bunazosine, β-antagonists such as propranolol andα/β-antagonists such as labetalol and carvedilol, (e) endothelinreceptor antagonists, (f) nitric oxide donors/releasing moleculesincluding organic nitrates/nitrites such as nitroglycerin, isosorbidedinitrate and amyl nitrite, inorganic nitroso compounds such as sodiumnitroprusside, sydnonimines such as molsidomine and linsidomine,nonoates such as diazenium diolates and NO adducts of alkanediamines,S-nitroso compounds including low molecular weight compounds (e.g.,S-nitroso derivatives of captopril, glutathione and N-acetylpenicillamine) and high molecular weight compounds (e.g., S-nitrosoderivatives of proteins, peptides, oligosaccharides, polysaccharides,synthetic polymers/oligomers and natural polymers/oligomers), as well asC-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds andL-arginine, (g) ACE inhibitors such as cilazapril, fosinopril andenalapril, (h) ATII-receptor antagonists such as saralasin and losartin,(i) platelet adhesion inhibitors such as albumin and polyethylene oxide,(j) platelet aggregation inhibitors including aspirin and thienopyridine(ticlopidine, clopidogrel) and GP IIb/IIIa inhibitors such as abciximab,epitifibatide and tirofiban, (k) coagulation pathway modulatorsincluding heparinoids such as heparin, low molecular weight heparin,dextran sulfate and β-cyclodextrin tetradecasulfate, thrombin inhibitorssuch as hirudin, hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone)and argatroban, FXa inhibitors such as antistatin and TAP (tickanticoagulant peptide), Vitamin K inhibitors such as warfarin, as wellas activated protein C, (l) cyclooxygenase pathway inhibitors such asaspirin, ibuprofen, flurbiprofen, indomethacin and sulfinpyrazone, (m)natural and synthetic corticosteroids such as dexamethasone,prednisolone, methprednisolone and hydrocortisone, (n) lipoxygenasepathway inhibitors such as nordihydroguairetic acid and caffeic acid,(o) leukotriene receptor antagonists, (p) antagonists of E- andP-selectins, (q) inhibitors of VCAM-1 and ICAM-1 interactions, (r)prostaglandins and analogs thereof including prostaglandins such as PGE1and PGI2 and prostacyclin analogs such as ciprostene, epoprostenol,carbacyclin, iloprost and beraprost, (s) macrophage activationpreventers including bisphosphonates, (t) HMG-CoA reductase inhibitorssuch as lovastatin, pravastatin, fluvastatin, simvastatin andcerivastatin, (u) fish oils and omega-3-fatty acids, (v) free-radicalscavengers/antioxidants such as probucol, vitamins C and E, ebselen,trans-retinoic acid and SOD mimics, (w) agents affecting various growthfactors including FGF pathway agents such as bFGF antibodies andchimeric fusion proteins, PDGF receptor antagonists such as trapidil,IGF pathway agents including somatostatin analogs such as angiopeptinand ocreotide, TGF-β pathway agents such as polyanionic agents (heparin,fucoidin), decorin, and TGF-β antibodies, EGF pathway agents such as EGFantibodies, receptor antagonists and chimeric fusion proteins, TNF-αpathway agents such as thalidomide and analogs thereof, Thromboxane A2(TXA2) pathway modulators such as sulotroban, vapiprost, dazoxiben andridogrel, as well as protein tyrosine kinase inhibitors such astyrphostin, genistein and quinoxaline derivatives, (x) MMP pathwayinhibitors such as marimastat, ilomastat and metastat, (y) cell motilityinhibitors such as cytochalasin B, (z) antiproliferative/antineoplasticagents including antimetabolites such as purine analogs (e.g.,6-mercaptopurine or cladribine, which is a chlorinated purine nucleosideanalog), pyrimidine analogs (e.g., cytarabine and 5-fluorouracil) andmethotrexate, nitrogen mustards, alkyl sulfonates, ethylenimines,antibiotics (e.g., daunorubicin, doxorubicin), nitrosoureas, cisplatin,agents affecting microtubule dynamics (e.g., vinblastine, vincristine,colchicine, paclitaxel and epothilone), caspase activators, proteasomeinhibitors, angiogenesis inhibitors (e.g., endostatin, angiostatin andsqualamine), rapamycin, cerivastatin, flavopiridol and suramin, (aa)matrix deposition/organization pathway inhibitors such as halofuginoneor other quinazolinone derivatives and tranilast, (bb)endothelialization facilitators such as VEGF and RGD peptide, and (cc)blood rheology modulators such as pentoxifylline.

Numerous additional therapeutic agents useful for the practice of thepresent invention are also disclosed in U.S. Pat. No. 5,733,925 assignedto NeoRx Corporation, the entire disclosure of which is incorporated byreference.

A wide range of therapeutic agent loadings can be used in connectionwith the medical devices of the present invention, with thetherapeutically effective amount being readily determined by those ofordinary skill in the art and ultimately depending, for example, uponthe condition to be treated, the age, sex and condition of the patient,the nature of the therapeutic agent, the nature of the medical deviceincluding the nature of its multilayer region(s), and so forth.

Further specific embodiments of the invention will now be described withreference to the Figures.

Referring now to FIGS. 1A-1C, one embodiment of the construction of aballoon catheter will now be described. Because polyelectrolytemultilayers containing SWNT have been measured to have an ultimatestrength of 220 Mpa (similar to PET film), the embodiment of theinvention described in these figures utilizes a destroyable mold for theformation of the multilayer region. In other embodiments, of course, theballoon can be made using a substrate that is not ultimately destroyed,such as a two-piece, releasable mold or such as a pre-existing balloonthat is incorporated into the device.

Turning now to FIG. 1A, an assembly is illustrated which includes a“lost core” mold 140, an inner guidewire lumen 110 and an outerinflation lumen 120, although it will immediately become clear on one ofordinary skill in the art that the balloon can built independently ofthe guidewire and inflation lumens. Guidewire and inflation lumens arewell known in the art and are commonly formed from materials such asnylons including nylon 12, thermoplastic polyester elastomers (e.g.,Hytrel®), polyether-block co-polyamide polymers (e.g., Pebax®), highdensity polyethylene, and polyurethane. Guidewire lumens are commonlyprovided with lubricious materials on their inner surfaces, for example,polytetrafluoroethylene or high density polyethylene.

In the next step, a multilayer coating 130, containing multiplealternating layers of polyelectrolyte (e.g., PEI) and nanoparticles(e.g., SWNT), is applied over the mold 140 as illustrated in FIG. 1B.Note that, in this embodiment, the multilayer coating 130 extends beyondthe proximal end (left end) of the mold 140, where it engages the outerinflation lumen 120, and extends beyond the distal (right) end of themold 140, where it engages the inner guidewire lumen 110.

Finally, the mold 140 is removed, thereby providing a finished ballooncatheter having an inner guidewire lumen 110, an outer inflation lumen120, and a multilayer balloon 130 as illustrated in FIG. 1C.

Of course innumerable variations on the above themes are possible.

For example, in the above steps, the multilayer coating 130 is formednot only on the wax mold 140, but also over a portion of the guidewirelumen 110 and the outer inflation lumen 120. As a result a separate stepis avoided for sealing the balloon 130 to the lumens 110, 120. In otherembodiments, on the other hand, the balloon is independently formed andsubsequently attached to the lumens 110, 120.

As another example, a braiding, winding or fiber meshwork, preferablyhaving a charged surface to ensure optimal adherence to subsequentlyassembled layers, can be provided on top of the wax mold. The braiding,winding or fiber meshwork can also be provided after severalpolyelectrolyte and/or nanoparticle layers have been deposited, ifdesired.

As another example, the mold of FIG. 1A can be extended to the proximalside of the assembly (not shown), thereby allowing part of the outerlumen to be constructed using the layer-by-layer technology. In fact, anentire outer lumen can be constructed in this fashion. Similarly, it isalso possible to build the tip of the inner lumen in the same fashion.

With reference now to FIGS. 3A-3C, in other embodiments, the finishedballoon 330 can be provided with longitudinal perfusion channels, forexample, by longitudinally placing tubes 350 inside the wax mold 340, asillustrated in the assembly of FIG. 3A. As can be seen from FIG. 3A, thetubes 350 protrude out of both sides of the wax mold 340.

A multilayer coating 330 containing multiple alternating polyelectrolyteand nanoparticle layers is then applied over the assembly as shown inFIG. 3B.

Finally, the wax mold 340 is removed, thereby providing a finishedballoon catheter having an inner guidewire lumen 310, an outer inflationlumen 320, and a multilayer balloon 330, as illustrated in FIG. 3C. Notethat the tubes 350 are incorporated into the balloon structure, formingperfusion channels. The protruding ends of the tubes 350 aresubsequently be trimmed as desired. Note than such tubes 350 can also beused as guidewire lumens, if desired, rendering the inner tube 310 inthe structure superfluous.

Balloons made by procedures such as those discussed herein are designedto be flexible, strong, non-compliant and durable (e.g., having goodpuncture and abrasion resistance). Of course, the present invention hasapplicability to a wide range of medical devices other than ballooncatheters.

Referring now to FIGS. 2A-2D, the encapsulation of a stent (i.e., theformation of a stent graft) will now be described. As in FIGS. 1A-1C and3A-3C above, the mold illustrated in FIG. 2A is a removable mold 240made, for example, from a material such as dental wax. The mold 240 inthis embodiment is in the form of an annulus and is positioned insidethe stent 220. The outer surfaces of the struts of the stent 220 remainuncovered by the mold 240 as shown.

As illustrated in FIG. 2B, a first multilayer coating 230 a, whichcontains multiple alternating polyelectrolyte and nanoparticle layers,is then applied over the mold 240 and stent 220, using, for example,techniques such as those described above.

The wax mold 240 is then removed, yielding the structure illustrated inFIG. 2C. Of course, a multilayer coating could be provided on the insideof the stent by placing a mold, or some other removable substrate suchas a polymeric wrap, on the outside of the stent structure.

In some embodiments, it is desirable to apply multilayer coatings onboth the outside and the inside of the stent structure. For example, asecond multilayer coating 230 b, which, like coating 230 a, containsmultiple alternating polyelectrolyte and nanoparticle layers, can beapplied to the inside of the structure of FIG. 2C, using the stent 220and multilayer coating 230 a as a substrate for the layer assembly. Thisyields the encapsulated stent structure of FIG. 2D. Note that themultilayer coating 230 a,b extends beyond both ends of the stent 220 inthe embodiment shown.

As with the balloons above, innumerable variations on the above themesare possible. For example, instead of using a lost-wax method to buildthe graft, it is also possible to add additional layers to an existinggraft using the techniques described herein.

Stent grafts formed in accordance with the present invention can bedelivered to a subject by a variety of known stent delivery systems,including various balloon catheters for stent delivery. In someembodiments, stent grafts can be delivered using a catheter thatcontains a multilayer balloon, also formed in accordance with thepresent invention.

Example 1

A mold 3 mm in diameter of polyvinyl alcohol (PVOH) series C-5(purchased from Adept Polymers Limited, London) is insert molded at 190°C. A metal core pin is embedded through the center of the mold.

The following solutions/suspensions are prepared: (1) PolyurethanePellethane 70D (Dow Chemical, Midland, Mich.) in Tetrahydrofuran (THF)at a concentration of 5%; (2) polyethylenimine (PEI) (Aldrich) in waterat a concentration of 1%; (3) polyacrylic acid (PAA) (Aldrich) in waterat a concentration of 1%; and (4) carbon nanotubes (CNT) (Carbolex,Inc., Lexington, Ky., USA) in water at a concentration of 0.6%. The CNTare functionalized by refluxing them in nitric acid.

A first layer of the polyurethane is deposited (by dipping) on the PVOHcore. Then, a layer of PEI is deposited on top of the polyurethanelayer. After this, 204 layers are deposited by repeating the followingsequence seventeen times:PAA-PEI-CNT-PEI-CNT-PEI-CNT-PEI-CNT-PEI-CNT-PEI. The PAA layers areintroduced to reinforce the electrostatic attraction.

After deposition of the layers, the metal core pin is pulled out of themold and water at a temperature of 60° C. is flushed for 2 hours throughthe opening left by the core pin, thus dissolving the PVOH core.

Example 2

The procedures of Example 1 are followed, with the following changes:Instead of the core and the first polyurethane layer, an existing PEBAX7233 single wall balloon (Boston Scientific Corp.) is used as anon-removable substrate. First, a layer of PEI deposited on the balloon.After this, 96 layers are deposited by following the following sequenceeight times: PAA-PEI-CNT-PEI-CNT-PEI-CNT-PEI-CNT-PEI-CNT-PEI. As above,the PAA layers reinforce the electrostatic attraction between thelayers.

Although various embodiments of the invention are specificallyillustrated and described herein, it will be appreciated thatmodifications and variations of the present invention are covered by theabove teachings without departing from the spirit and intended scope ofthe invention.

1. A medical device comprising a multilayer region that comprises: (a) acharged nanoparticle layer comprising charged nanoparticles; (b) aplurality of charged polyelectroyte layers comprising chargedpolyelectrolyte species, and (c) at least one charged therapeutic agent,wherein said medical device is configured for implantation or insertioninto a subject.
 2. The medical device of claim 1, wherein said medicaldevice is selected from a balloon catheter, a graft, a stent and afilter.
 3. The medical device of claim 1, wherein said multilayer regioncomprises a plurality of charged nanoparticle layers.
 4. The medicaldevice of claim 1, said multilayer region comprises a plurality ofcharged nanoparticle layers that comprise nanoparticles selected fromcarbon nanoparticles, silicate nanoparticles, and ceramic nanoparticles.5. The medical device of claim 1, wherein said multilayer regioncomprises a plurality of charged nanoparticle layers that comprisenanoparticles selected from carbon nanotubes, carbon nanofibers,fullerenes, ceramic nanotubes, ceramic nanofibers, phyllosilicates,monomeric silicates and dendrimers.
 6. The medical device of claim 1,wherein said multilayer region comprises a plurality of chargednanoparticle layers that comprise single walled carbon nanotubes.
 7. Themedical device of claim 1, wherein said multilayer region comprises aplurality of charged nanoparticle layers that comprise nanoparticlesranging from 0.5 to 100 nm in smallest dimension.
 8. The medical deviceof claim 1, wherein said multilayer region comprises a plurality ofcharged polyelectrolyte layers that comprise a polycation selected frompolyallylamine, polyethyleneimine, poly(dimethyl diallyl ammoniumchloride), protamine sulfate, chitosan, gelatin, spermidine, andalbumin, and a plurality of charged polyelectrolyte layers that comprisea polyanion selected from poly(styrene sulfonic acid), poly(anilinesulfonic acid), polyacrylic acid, sodium alginate, polystyrenesulfonate, eudragit, gelatin, hyaluronic acid, carrageenan, chondroitinsulfate, carboxymethylcellulose.
 9. The medical device of claim 1,wherein said multilayer region comprises from 10 to 200 chargedpolyelectrolyte and nanoparticle layers.
 10. (canceled)
 11. The medicaldevice of claim 1, wherein a protective polymer coating layer isprovided over at least a portion of said multilayer region.
 12. Themedical device of claim 1, wherein said plurality of chargedpolyelectrolyte layers comprises a biodegradable charged polyelectrolytelayer.
 13. The medical device of claim 12, wherein said chargedtherapeutic agent is provided beneath or within said biodegradablepolyelectrolyte layer.
 14. The medical device of claim 1, wherein saidmedical device comprises a plurality of said multilayer regions.
 15. Themedical device of claim 1, wherein at least a portion of said multilayerregion is freestanding.
 16. The medical device of claim 1, wherein atleast a portion of said multilayer region is disposed on an underlyingor overlying structure.
 17. The medical device of claim 16, wherein saidunderlying or overlying structure is a temporary structure that is notimplanted or inserted with said medical device.
 18. The medical deviceof claim 16, wherein said underlying or overlying structure is apermanent structure that forms part of said medical device.
 19. Themedical device of claim 16, wherein said underlying structure is aballoon.
 20. The medical device of claim 16, wherein said underlyingstructure is a catheter.
 21. The medical device of claim 16, whereinsaid underlying structure is a stent.
 22. The medical device of claim16, wherein said underlying structure is a graft.
 23. The medical deviceof claim 16, wherein a patterned multilayer region is provided over saidunderlying structure.
 24. The medical device of claim 16, wherein saidunderlying structure is a ceramic,
 25. A medical device comprising amultilayer region, the multilayer region comprising: a) a chargednanoparticle layer comprising charged nanoparticles; and (b) a pluralityof charged polyelectroyte layers comprising charged polyelectrolytespecies, wherein one or more reinforcement members are provided adjacentto or within said multilayer region, said device is configured forimplantation or insertion into a subject.
 26. The medical device ofclaim 25, wherein said one or more reinforcement members are in the formof a fiber mesh, a fiber braid or a fiber winding.
 27. A medical devicecomprising a multilayer region, the multilayer region comprising: a) acharged nanoparticle layer comprising charged nanoparticles; and (b) aplurality of charged polyelectroyte layers comprising chargedpolyelectrolyte species, the medical device further comprising a residuefrom a removable substrate adjacent said multilayer region.
 28. Amedical device comprising a multilayer region, the multilayer regioncomprising: a) a charged nanoparticle layer comprising chargednanoparticles; and (b) a plurality of charged polyelectroyte layerscomprising charged polyelectrolyte species, wherein chargednanocapsules, which comprise a plurality of charged polyelectrolyteencapsulation layers, are incorporated into said multilayer region. 29.The medical device of claim 28, wherein said charged nanocapsulescomprise a therapeutic agent.
 30. The medical device of claim 1, whereinsaid therapeutic agent is selected from anti-thrombotic agents,anti-proliferative agents, anti-inflammatory agents, anti-migratoryagents, agents affecting extracellular matrix production andorganization, antineoplastic agents, antimitotic agents, anestheticagents, anti-coagulants, vascular cell growth promoters, vascular cellgrowth inhibitors, cholesterol-lowering agents, vasodilating agents, andagents that interfere with endogenous vasoactive mechanisms. 31-52.(canceled)
 53. The medical device of claim 1, wherein said medicaldevice comprises a balloon that is configured for insertion into andinflation within a body lumen of a subject, said balloon comprising amultilayer region that further comprises: (a) at least five chargednanoparticle layers comprising charged carbon nanotubes; and (b) atleast five charged polyelectroyte layers comprising chargedpolyelectrolyte species.
 54. The medical device of claim 53, whereinsaid charge polyelectrolyte layers are selected from polyacrylic acid,polyethylene imine, or a combination of both.
 55. The medical device ofclaim 53, further comprising an inflatable balloon underlying saidmultilayer region.
 56. The medical device of claim 53, furthercomprising a fibrous reinforcement member.
 57. A medical devicecomprising a multilayer region, the multilayer region comprising: (a) acharged nanoparticle layer comprising charged nanoparticles; and (b) aplurality of charged polyelectroyte layers comprising chargedpolyelectrolyte species, wherein at least a portion of said multilayerregion is free standing, and said medical device is configured forimplantation or insertion into a subject.
 58. A medical devicecomprising a multilayer region that comprises: (a) a chargednanoparticle layer comprising charged nanoparticles; (b) a plurality ofcharged polyelectroyte layers comprising charged polyelectrolytespecies, (c) at least one therapeutic agent, and (d) at least oneprotective coating is provided over at least a portion of the multilayerregion, wherein said medical device is configured for implantation orinsertion into a subject.
 59. A medical device comprising a multilayerregion that comprises: (a) a charged nanoparticle layer comprisingcharged nanoparticles; (b) a plurality of charged polyelectroyte layerscomprising charged polyelectrolyte species, and (c) one or morereinforcement members provided adjacent to or within said multilayerregion, said reinforcement members are in the form of a fiber mesh, afiber braid or fiber winding, wherein said medical device is configuredfor implantation or insertion into a subject.
 60. A medical devicecomprising a multilayer region that comprises: (a) a chargednanoparticle layer comprising charged nanoparticles; (b) a plurality ofcharged polyelectroyte layers comprising charged polyelectrolytespecies, and (c) charged nanocapsules incorporated into said multilayerregion, said charged nanocapsules comprise a therapeutic agent, whereinsaid medical device is configured for implantation or insertion into asubject.